The development of long-term slow-release injections capable of continuously releasing a drug has hitherto been investigated with the aim of minimizing the number of times a medication is administered and thus improving drug compliance. In particular, numerous studies have been conducted on methods of controlled release involving the use of drug microspheres (sometimes abbreviated below as “MS”) that use a polymer having a poor solubility in water. A biodegradable polymer is employed as this polymer so that, following release of the drug, the base does not remain at the site of administration. In particular, use is made of polylactic acid polymers (sometimes abbreviated below as “PLA”) or lactic acid/glycolic acid copolymers (sometimes abbreviated below as “PLGA”), which have an established record of use in, for example, surgical suture thread and bone-anchoring bolts. These polymers are employed in injections of the LH-RH derivative Leuplin (trade name), which are commercially sold as slow-release injections, and in the long-acting somatostatin derivative Sandostatin (trade name) LAR.
Drugs commonly encapsulated within microspheres include peptides, proteins and nucleic acids, such as physiologically active peptides, various types of hormones, growth factors, antibodies, genes and various cell growth/differentiation factors. In the manufacture of microspheres, in general it is known that when the drug to be encapsulated has a higher molecular weight, microspheres which have a low initial burst and the release of which is easily controlled can be more easily manufactured.
By contrast, for a number of reasons, including the large initial burst, the difficulty of controlled release and the low drug content (encapsulation ratio), great difficulty has been encountered in efforts to prepare microspheres containing low-molecular-weight drugs; carrying out the stable release of such drugs in vivo and controlling the rate of release has proven to be exceedingly difficult. As a result, while there are cases in which low-molecular-weight compounds have been encapsulated (see Patent Document 1), none are available commercially as pharmaceutical preparations.
Meanwhile, the compound, ({5-[2-({[(1E)-phenyl(pyridin-3-yl)methylene]amino}oxy)ethyl]-7,8-dihydronaphthalen-1-yl}oxy)acetic acid (abbreviated below as “the present drug”) is a low-molecular-weight compound which has a chemically stable non-prostaglandin (PG) skeleton, a PGI2 receptor (IP) agonist action and a thromboxane (TX) A2 synthetase inhibition activity. The present drug, because it has a PGI2 agonist action, is known to be used in the prevention and/or treatment of, for example, thrombosis, arteriosclerosis, ischemic heart disease, gastric ulcers and hypertension (Patent Document 2).
However, concerns when the present drug is administered orally include side effects such as upper abdominal pain and diarrhea. When administered intravenously, side effects such as a hypotensive action associated with vasodilation, flushing and headaches, etc. are a concern. In particular, when the present drug is employed for, of the above-mentioned diseases, cardiovascular diseases such as arteriosclerosis and ischemic heart disease, etc. from the standpoint of the side effects and the therapeutic system, to prevent exposure to a high concentration of the drug in the digestive tract and a sudden rise in the blood concentration of the drug, to minimize the burden on the patient and to maximize the drug effects, there exists a keen desire for preparations which are capable of continuously maintaining the drug concentration with the smallest possible number of administration, including dosage forms of a type that continuously maintain the concentration of the drug in the tissue at the site of disease or blood concentration maintenance-type dosage forms such as intravenous drip infusions.
The local administration of microspheres containing the present drug has been investigated as a method for resolving the above problems, including the appearance of side effects and a sudden rise in the blood concentration of the drug. For example, Patent Document 3 discloses a long-acting preparation containing the present drug and PLGA, and states that this preparation was effective when locally administered in a rat arteriosclerosis obliterans (ASO) model. However, because the microspheres described in Patent Document 3 had a low drug content, the dose in which the microspheres themselves are administered increases, giving rise to an acidy problem. In addition, the release period for the present drug is short and the rate of release is not constant, as a result of which these prior-art microspheres have not succeeded in maintaining the blood concentration optimal for emergence of the drug effects over a fixed period of time.
Patent Document 1: JP-9-263545 A
Patent Document 2: JP-6-87811 A
Patent Document 3: WO 2004/032965